TY - JOUR T1 - Regulator of G Protein Signaling Protein Suppression of Gα<sub>o</sub> Protein-Mediated α<sub>2A</sub> Adrenergic Receptor Inhibition of Mouse Hippocampal CA3 Epileptiform Activity JF - Molecular Pharmacology JO - Mol Pharmacol SP - 1222 LP - 1230 DO - 10.1124/mol.108.054296 VL - 75 IS - 5 AU - Brianna L. Goldenstein AU - Brian W. Nelson AU - Ke Xu AU - Elizabeth J. Luger AU - Jacquline A. Pribula AU - Jenna M. Wald AU - Lorraine A. O'Shea AU - David Weinshenker AU - Raelene A. Charbeneau AU - Xinyan Huang AU - Richard R. Neubig AU - Van A. Doze Y1 - 2009/05/01 UR - http://molpharm.aspetjournals.org/content/75/5/1222.abstract N2 - Activation of G protein-coupled α2 adrenergic receptors (ARs) inhibits epileptiform activity in the hippocampal CA3 region. The specific mechanism underlying this action is unclear. This study investigated which subtype(s) of α2ARs and G proteins (Gαo or Gαi) are involved in this response using recordings of mouse hippocampal CA3 epileptiform bursts. Application of epinephrine (EPI) or norepinephrine (NE) reduced the frequency of bursts in a concentration-dependent manner: (-)EPI &gt; (-)NE &gt;&gt;&gt; (+)NE. To identify the α2AR subtype involved, equilibrium dissociation constants (pKb) were determined for the selective αAR antagonists atipamezole (8.79), rauwolscine (7.75), 2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane hydrochloride (WB-4101; 6.87), and prazosin (5.71). Calculated pKb values correlated best with affinities determined previously for the mouse α2AAR subtype (r = 0.98, slope = 1.07). Furthermore, the inhibitory effects of EPI were lost in hippocampal slices from α2AAR-but not α2CAR-knockout mice. Pretreatment with pertussis toxin also reduced the EPI-mediated inhibition of epileptiform bursts. Finally, using knock-in mice with point mutations that disrupt regulator of G protein signaling (RGS) binding to Gα subunits to enhance signaling by that G protein, the EPI-mediated inhibition of bursts was significantly more potent in slices from RGS-insensitive GαoG184S heterozygous (Gαo+/GS) mice compared with either Gαi2G184S heterozygous (Gαi2+/GS) or control mice (EC50 = 2.5 versus 19 and 23 nM, respectively). Together, these findings indicate that the inhibitory effect of EPI on hippocampal CA3 epileptiform activity uses an α2AAR/Gαo protein-mediated pathway under strong inhibitory control by RGS proteins. This suggests a possible role for RGS inhibitors or selective α2AAR agonists as a novel antiepileptic drug therapy. The American Society for Pharmacology and Experimental Therapeutics ER -